Water-soluble biologically active ammonium salts

ABSTRACT

This invention relates to hydrolysis resistant, water-soluble ammonium salt solids which are biologically active and which are described by the formula ##STR1## wherein m has a value of from 1 to 3; n has a value of from 1 to 4 and is equal to the free valences in anion R; p has a value of from 1 to 3; R 1 , R 2  and R 3  are each independently selected from the group of hydrogen, and C 1  to C 2  alkyl; R 5  and R 6  are each independently selected from the group of hydrogen, hydroxyalkyl and alkoxyalkyl radicals having from 1 to 10 carbon atoms and R is the anion of a biologically active, water-insoluble anion having at least 1 deprotonized hydrogen and is derived from a biologically active, acidic, organic compound selected from the group of a carboxylic, thiocarbonic, sulfonic, sulfinic, thiosulfonic, thioacid, mono- and di- thiophosphate and phosphorous containing acid, having a pKa* value less than 5.

In one aspect the invention relates to stable, water soluble ammoniumsalts derived from water-insoluble, biologically active materials. Inanother aspect, the invention relates to the selective production of astable, water-soluble pharmaceutical, herbicide, fungicide, insecticide,fumigant, or plant growth regulant in the form of a salt which has asignificantly higher pH than its corresponding biologically activecompound. Still another aspect of the invention pertains to compositionscontaining instant salt products and their use in specific fields ofapplication dictated by the anionic moiety of said salt.

BACKGROUND OF THE INVENTION

Many organic carboxylic, phosphorous and/or sulfur-containing compoundsare known to have superior biological properties which are beneficial inagricultural applications as insecticides, fungicides, fumigants andplant growth regulants; however, wide spread use of many of theseproducts has been hampered by their water-insolubility. To overcome thisproblem, it has been necessary to form compositions involving the use ofseveral components including surfactants, stabilizers and organicsolvents, most of which are toxic or potentially toxic to animal, plantor marine life. Another solution to the problem is to form complexes ofthe water-insoluble chemicals with ammonia long chain amines or othersolubilizing complexing agents. These methods have not resulted in acompletely satisfactory solution since extraneous chemicals introducesome undesirable side effects and dilute the efficacy of the desiredactive component. It is particularly noted that the formulationscontaining surfactants cannot be used as aquatic herbicides or algicidessince the surfactants have a deleterious affect on fish life. Complexesof the above water-insoluble biocides are also objectionable since theyare easily hydrolyzed and must be applied shortly after complexformation. Hence, it has been the aim of research to provide suchefficacious biologically active agents in a form which is resistant tohydrolysis for a more enduring effect and which is water-soluble tofacilitate monitored dosage in aqueous sprays, most useful inagricultural applications.

Aqueous drug solutions have also attracted much interest in the field oflocal and systemic chemotherapy since such solutions introduce noextraneous or toxic chemicals and provide better drug penetration and amore immediate effect than tablet or capsule administration. However, nocompletely satisfactory solution has yet been developed, and the searchcontinues for hydrolysis resistant, water soluble forms of normallywater-insoluble pharmaceutical and agricultural chemicals which areeasily manufactured and have good storage life.

Accordingly, it is an object of this invention to remedy the abovedeficiencies of biologically active water-insoluble compounds and toproduce said compounds in a form which is resistant to hydrolysis and issubstantially soluble in water.

Another object of this invention is to provide an economical,commercially feasible process for the preparation of said water soluble,hydrolysis resistant, biochemicals and drugs.

Still another object of the invention is to provide a product of highefficacy which is specific to plant life, fungus infection or insectattack and which does not require the use of a surfactant in itsformulation.

These and other objects of the invention will become apparent to oneskilled in the art from the following description and disclosure.

THE INVENTION

This invention relates to hydrolysis resistant, water-soluble ammoniumsalt solids which are biologically active and which are described by theformula ##STR2## wherein m has a value of from 1 to 3; n has a value offrom 1 to 4 and is equal to the free valences in anion R; p has a valueof from 1 to 3; R₁, R₂ and R₃ are each independently selected from thegroup of hydrogen, and C₁ to C₂ alkyl; R₅ and R₆ are each independentlyselected from the group of hydrogen, hydroxyalkyl and alkoxyalkylradicals having from 1 to 10 carbon atoms and R is the anion of abiologically active, water-insoluble organic compound having at least 1deprotonized hydrogen and is derived from a biologically active,organic, acidic compound having from 2 to 24 carbon atoms which isselected from the group of a carboxylic, thiocarbonic, sulfonic,sulfinic, thiosulfonic, thioacid, arsanilic, mono- and di-thiophosphateand phosphorous containing acids and which has a pKa less than 5.

Of the above compounds, those having a pKa less than 4 and wherein R₁,R₂ and R₃ are hydrogen; n has a value of not more than 2 and R is acarboxylate, phosphate, phosphonate, thiophosphate, sulfonate, orarsanilate anion are preferred.

The water-soluble biologically active compounds referred to herein arethose containing an acidic hydrogen which is capable of quaternizing theterminal nitrogen of the present lactam alkyl amine forming salt byprotonization. These organic compounds having a protonizable hydrogeninclude carboxylic, thiocarbonic, sulfonic, sulfinic, thiosulfonic,thioloc and phosphorous containing acids shown on pages 528 through 534of VAN NOSTRAND CHEMIST'S DICTIONARY, 1961. Representative examples ofthese biologically active compounds are listed in the following Tablewhere the number of effectively dissociatable acidic hydrogen atoms areshown in parenthesis. ##STR3##

Examples of water-insoluble pharmaceutical compounds having at least oneacidic hydrogen include the following compounds wherein the number ofdissociatable hydrogen atoms is shown in parenthesis.

    ______________________________________                                        Ibuprofen (1),    Indoprofen (1),                                             Indobufen (1),    Indomethacin (1),                                           Clavulinic acids (1),                                                                           Aconiazide (1),                                             Acrivastine (1),  Acidic Aldesulfone (1,2),                                   Amineptine (1),   Acetyl salicylic acid (1),                                  Acetiromate (1),  Acexamic acid (10,                                          Acidic Aceflylline (1),                                                                         Acifran (1),                                                Acipimox (1),     Aminobenzoic acid (1),                                      Amoxicillin (1),  Benfotiamine,                                               Ceforamide (1,2), Acidic Chiniofon (1),                                       Dinoprostone (1), Acidic Docusate (1),                                        Etidronic acid (1,2,3,4),                                                                       Fosfosal (1,2,3),                                           Fosfocreatinine (1,2),                                                                          Carbarsone (1,2),                                           Isotretinoin (1), Halazone (1),                                               Methyl dopa (1),  Meticillin (1),                                             Nalidixic acid (1),                                                                             Nedocromil (1,2),                                           Acidic Cyclamate (1),                                                                           Sulfoniazide (1),                                           Sulisatin (1,2) and                                                                             Phosphinic acid (1),                                        Thiobromineacetic acid (1),                                                                     Thenoic acid (1),                                           Sulisobenzene (1),                                                                              Sulindac (1),                                               Phthalic acid (1,2),                                                                            Phosphocreatine (1,2,3), and                                Phytonadiol diphosphoric acid                                                 [Vitamin K-acid form (1,2,3,4)].                                              ______________________________________                                    

The above pharmaceuticals include antibiotics, antidepressants,amebicides, antiseptics, disinfectants, laxatives, tonics, andantiiinflammatory, antihyperlipemic, antitubercular, antileprotic,antiasthamatic, dermological, antiprotozoal, analgesic, cardial,antiacne, antihypertensive and antiallergic agents.

The present products are characterized as having a hydrophilic moiety,represented by the quaternized pyrrolidonyl alkyl ammonium moiety whichis electrostatically bonded to the anion and is thus significantly moresoluble in water than the parent biologically active material Thefunction of the product is specifically controlled by the selection ofanion used to form the present ammonium salt. Of course, it is to beunderstood that mixtures of the present salts can be employed when oneor more functions are desired.

The products of the present application are prepared by an economicaland commercially feasible process which involves dissolving thewater-insoluble component in a non-aqueous inert solvent such as forexample, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone,acetonitrile, toluene, methylene chloride, and the like or forming asuspension of the water-insoluble component in water and then contactingwith the selected, non-quaternized lactam alkyl amine having the formula##STR4## which is reacted at a temperature of between about 20° andabout 90° C. under a pressure of from about atmospheric to about 50psig. over a period of from about 10 minutes to about 2 hours. Preferredreaction parameters include a temperature of between about 30° C. andabout 50° C. under atmospheric pressure for a period of from about 20minutes to about 1 hour. When a non-aqueous solvent is employed, it isremoved by evaporation or any other convenient method, for example byfiltration in those cases where the resulting salt is insoluble in theorganic solvent. Aqueous solutions of the products can be employed assuch, or with additional dilution or concentration as needed, to performtheir desired functions. Generally, the reaction solvent or dispersingagent employed in the synthesis reaction is present in a concentrationof between about 10 wt. % and about 90 wt. %, preferably between about30 wt. % and about 70 wt. %.

The mole ratio of the non-quaternized N-pyrrolidonyl alkyl amine tobiologically active component ranges between about 1:1 and about 4:1,preferably between about 1:1 and about 2:1. Most preferably, the molaramount of reactant pyrrolidonyl alkyl amine is about equal to one or twoof the hydrogen atoms in the biologically active or pharmaceuticalcompound. While sufficient pyrrolidonyl reactant can be used toquaternize all sites of dissociable and protonizable hydrogen atoms incompounds containing 4 or more acidic hydrogen atoms, reaction at morethan two sites is usually not required to provide the desired watersolubility in the product.

The products of the present invention can be used as aqueousdispersions, emulsions or solutions without further purification or theymay be dried and used as granules, a fine powder or can be molded intotablets or the like. For agricultural applications, the present productsare beneficially applied as aqueous solutions, emulsions or dispersionswherein the concentration of the active product is between about 0.1 andabout 95%; more often between about 0.75 and about 50%. Formulations ofthe present products can include a surfactant, if desired, together withother adjuvants such as wetting agents, diluents, rheology modifiers,buffering agents, binders and disintegrating agents. Pharmaceuticalformulations generally include between about 0.01 and about 900 mg,preferably between about 1 and about 500 mg concentration of the presentproducts which can be administered as a tablet, capsule, powder, lotion,paste, or solution or in a formulation which may include other medicinalcomponents. Such formulations may be prepared by simply mixing thedesired components at ambient temperature and pressure.

Having thus described the invention, reference is now had to thefollowing examples which illustrate preferred embodiments but which arenot to be construed as limiting to the scope of the invention as morebroadly set forth above and in the appended claims.

EXAMPLE 1

A 500 ml round bottomed flask was charged with 150g of methanol to whichwas added 30 g commercially available (Dicamba) 3,6-dichloro-1-methoxybenzoic acid which was 90% pure. The mixture was stirred at roomtemperature until the complete dissolution occured. To the solution wasadded 15.8 g of 98.5% pure amino ethyl pyrrolidone (AEP) over a periodof 30 minutes during which a slight exhotherm occurred. The mixture wasthen stirred for about 30 minutes, after which the solvent was removedby rotary evaporation leaving a slightly oily product. The product waspurified by titurating with acetone (200-300 ml) until a whitecrystalline solid (m.p.=18°-20° C.) was produced weighing 28 g,representing a 65% yield of 99.5% pure N-pyrrolidonyl ethyl ammoniumsalt of 3,6-dichloro-1-methoxy benzoic acid.

The purity of the product was determined by potentiometric titration ofa methanolic solution of the salt by alkali (NaOH) and acid (HCl). Thecomposition of the product was established by elemental analysis,reported as follows:

    ______________________________________                                                     Calculated                                                                            Found                                                    ______________________________________                                        %        C         48.14     47.73                                                     H          5.16      5.25                                                     N          8.02      7.87                                                     Cl        20.34     20.42                                            ______________________________________                                    

IR (Infra red) spectra and ¹ H and ¹³ CNMR spectra were consistent withthe structure assigned.

A stable solution of the above ammonium salt was easily dissolved in 60%water; whereas the 3,6-dichloro-1-methoxy benzoic acid had very poorsolubility (<0.1%) in water.

EXAMPLE 2

Example 1 was repeated, except that 2 g of heavy water replaced 150 g ofmethanol solvent, 0.3 g of Dicamba replaced 30 g Dicamba and 0.16 g ofAEP replaced 15.8 g of AEP. The resulting ammonium salt of Dicamba hadthe same NMR spectral analysis as in Example 1 showing that the saltexists in solution even without isolation.

The above experiments show that the AEP salt can be easily solubilizedin water and can be prepared as a concentrated solution, which can bediluted to a desired concentration prior to application.

EXAMPLE 3

In a 250 ml round bottom flask 15.5 g (0.482 millimole) of a commercialherbicide, imazaquin* (97.4% pure, having an average molecular weight of311.4) was suspended in 100 g water. To the suspension, 6.1 g (0.469millimole) of 98.5% pure AEP was added. The mixture was stirred for 1hour and produced a clear solution within 15 minutes. The solution wasthen filtered through Whatman paper #4 and the pH of the filtrate wasfound to be 7.2. The filtrate was then freeze dried to produce 18.0 g ofthe hygroscopic solid ammonium salt of imazaquin. The freeze-dried solid(0.1 g), dissolved completely in 50 g of water, which established thesolubility of the ammonium salt product.2-[4,5-dihydro-4-methyl-4-(methylethyl)-5-oxo-1H-imidazol-2-yl]-3-quinolinee carboxylic acid.

The freeze-dried solid, was analyzed for its spectral properties via IRand ¹ H NMR spectral data. The spectral data indicate the structure ofthe N-pyrrolidonyl ethyl ammonium salt of imazaquin.

EXAMPLE 4

A solution containing 25 g of the AEP salt of commercial imazaquin inwater was prepared from a suspension of 25 g of imazaquin in 50 g waterto which was added a stoichiometric amount of AEP (10.2 g) and anadditional 15 g of water. The solution was stirred for 30 minutes afterwhich it was filtered and the pH of the filtrate was adjusted to 7.2.

The resulting solution was found to be stable under ambient conditionswithout any precipitation when stored for 6 months. Also, after coolingto 0° C. and then allowing to heat to room temperature, no precipitationwas observed.

The above experiment shows that 35% of the present ammonium salt ofwater insoluble imazaquin derived from 25% of the imazaquin can besolubilized in water as a stable AEP salt product and can bemanufactured as a useful, water-soluble concentrate.

EXAMPLE 5

To a solution containing 13 g (0.1 mole) AEP (98.5% pure) dissolved in30 g water in a 100 ml round bottom flask was added at 25° C. and withconstant agitation, 16.9 g (0.1 mole) of water insoluble solidphosphonomethyl glycine. The solid phosphonomethyl glycine reacted toform the corresponding AEP salt and completely dissolved in the waterwithin 30 minutes, during which an exhotherm to 35°-40° C. was noted.The water was removed by rotary evaporation, which produced an oilyliquid from which the pure salt product was isolated by tituration withmethanol and then with acetone followed by filtration and drying toproduce the AEP salt of phosphonomethyl glycine which is more than 50%soluble in water.

¹ H and ¹³ CNMR data indicated the structure of the product to be theN-pyrrolidonyl ethyl ammonium salt of phosphonomethyl glycerine. Thus,the water soluble salt of phosphonomethyl glycine can be produced andstored as a stable aqueous concentrate for subsequent use.

EXAMPLE 6

The commercial product "Spot Weeder", from Johnson Wax contains anaqueous solution of a wetting agent and an active mixture of herbicidaldimethyl amine salts of (a) 2,4-dichlorophenoxy acetic acid* (0.583%),(b) 2-(4-chloro-2-methylphenoxy) propanoic acid** (0.287%) and (c)3,6-dichloro-2-methoxy benzoic acid (0.066%).

For the purposes of experimentation, a water soluble composition wasmade containing the same mole percent of (a), (b) and (c) and formulatedas the corresponding AEP salts, by the addition of stoichiometricamounts of AEP to (a), (b) and (c) according to the following procedure.

To one liter of water was added 15.42 g of 2,4D+7.11 g of mecoprop+1.83g of 90% pure dicamba. After which 13.83 g AEP was added to the mixture.The resulting solution was stirred for 30 minutes to produce acompletely water soluble product of active ingredients in the form ofAEP salts. To the above solution was added 9 g of polyalkylene oxidemodified by polydimethyl siloxane (Silvelt 7607 wetting agent) fromUnion Carbide. The mixture was stirred and the total weight was adjustedto 3000 g by adding water.

This solution was compared with commercial "Spot Weeder" by spraying onside by side 10'×10' plots. The present salt showed distinct advantagesover "Spot Weeder" in that the rate of weed kill was significantlyhigher.

EXAMPLE 7

A suspension of 169 g of phosphonomethyl glycine in 301 g water wasprepared and 130 g 98.5% pure AEP was added slowly with stirring untilall of the phosphonomethyl glycine dissolved as the AEP salt. Theresulting solution, (containing 28% of the active ingredient expressedas the free acid or 49.5% of the active ingredient expressed as the AEPsalt) was evaluated as an aquatic herbicide and as a broad spectrumgrowth inhibitor for broad leaf plants and perennial weeds and comparedwith the isopropyl amine salt of phosphonomethyl glycine.

Results showed significantly higher and more permanent kill for thepresent AEP salt.

Following the procedure of the above examples, other lactam alkyl aminescan be substituted for AEP to produce the corresponding water solublesalts of the indicated water insoluble biologically active compounds.Particularly recommended as lactam amines are the aminopropylpyrrolidones, aminobutyl pyrrolidones, N,N'-di(hydroxyethyl) ethyl aminopyrrolidone, aminomethyl caprolactams and aminoethyl valerolactams.Similarily, other biologically active water insoluble compounds or drugshaving one or more acidic hydrogen atoms can be substituted in the aboveexamples, or with other lactam amines indicated herein, to providedesirable water soluble salts.

What is claimed is:
 1. A biologically active compound having the formula##STR5## wherein m has a value from 1 to 3; n has a value of from 1 to 4and is equal to the free valences in anion R; p has a value of from 1 to2; R₁, R₂ and R₃ are each independently selected from the group ofhydrogen, and C₁ to C₂ alkyl; R₅ and R₆ are each independently selectedfrom the group of hydrogen, hydroxyalkyl and alkoxyalkyl radicals havingfrom 1 to 10 carbon atoms and R is the anion of a biologically active,water-insoluble organic compound having at least 1 deprotonized hydrogenand derived from a biologically active carboxylic acid substitutedquinoline group having a pKa value less than
 5. 2. The compound of claim1, selected from the group consisting of 3,7-dichloro-8-quinolinecarboxylic acid and 2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-S-OXO-1H-imidazol-2-yl)-3 quinoline carboxylic acid.
 3. The compound of claim 1wherein R is an anion of imazaquin.